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US6258848B1 - Methods and compositions for increasing insulin sensitivity - Google Patents

Methods and compositions for increasing insulin sensitivity Download PDF

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US6258848B1
US6258848B1 US09/364,637 US36463799A US6258848B1 US 6258848 B1 US6258848 B1 US 6258848B1 US 36463799 A US36463799 A US 36463799A US 6258848 B1 US6258848 B1 US 6258848B1
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insulin
nac
glucose
insulin resistance
glucosamine
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I. George Fantus
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Mt Sinai Hospital
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Mt Sinai Hospital
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism

Definitions

  • the invention relates to methods and compositions for increasing insulin sensitivity.
  • Glucose homeostasis depends upon the balance between hepatic glucose production and glucose utilization by insulin-dependent tissues, such as fat, muscle and liver, and by insulin-independent tissues such as brain and kidney [Cahill G. F. Jr. (1976), J. Clin. Endocrinol. Metab. 5: 397-415; Bergman R. N. (1989), Diabetes. 38: 1512-1527].
  • pancreatic hormones insulin from the ⁇ -cell of the pancreatic islet and glucagon from the ⁇ -cell.
  • pancreatic hormones insulin from the ⁇ -cell of the pancreatic islet and glucagon from the ⁇ -cell.
  • an increased plasma glucose stimulates insulin secretion.
  • This increase in circulating insulin level promotes glucose utilization by peripheral tissues and inhibits hepatic glucose output.
  • Non-insulin-dependent diabetes mellitus is characterized by two pathological defects.
  • One defect is insulin resistance of the major target tissues [Himsworth H. and Kerr R. B. (1942), Clin. Sci. 4:120; Kahn C. R. (1978), Metabolism. 27: 1893-1902; Olefsky J. M. (1981), Diabetes. 30:148-161; Reaven G. M. (1988), Diabetes. 37: 1595-1607; Kahn C. R. et al., in Pathogenesis of Non-Insulin Dependent Diabetes Mellitus. Grill V, Efendic S. Eds. (1988) New York Raven p. 227-239; DeFronzo R.
  • Insulin resistance is generally defined as a reduced response to a given concentration of insulin. In Type II diabetes, this is manifested as a decreased ability of insulin to stimulate glucose uptake into muscle and fat, as well as to inhibit glucose production by the liver. In humans with obesity and Type II diabetes, there are multiple defects in insulin action including a decrease in insulin receptor and IRS-1 phosphorylation and a reduced PI 3-kinase activity [Defronzo R. A. et al (1992), Diabetes Care 15: 318-368; Kahn C. R. (1994), Diabetes 43:1066-1084; Kruszynska Y. T., Olefsky J. M. (1996), J. Invest Med. 44: 413-428].
  • Insulin resistance in adipocytes is characterized by a decrease in both maximum insulin responsiveness as well as insulin sensitivity of the glucose transport system [Kashiwagi A. et al (1983), J. Clin. Invest. 72: 1246-1254; Marshall S., Olefsky J. M. (1980), J. Clin. Invest. 66: 763-772; Ciaraldi T. P. et al (1982), Diabetes 31: 1016-1022; Kolterman G. et al (1981), J. Clin. Invest. 68: 957-969].
  • the hexosamine biosynthesis pathway in which fructose-6-phosphate is converted to glucosamine-6-phosphate, may be the pathway by which cells sense and respond to ambient glucose levels and, when glucose flux is excessive, down regulate glucose transport resulting in insulin resistant cells [Marshall, S., et al (1991), J. Biol Chem 266:4706-4712].
  • Glucose induced insulin resistance has been blocked by inhibiting glutamine:fructose-6-P amidotransferase (GFA), the rate-limiting enzyme of the hexosamine pathway [Marshall, S., et al (1991), J. Biol Chem 266:4706-4712].
  • Glucosamine an agent known to preferentially enter the hexosamine pathway at a point distal to enzymatic amidation by GFA, bypasses the blockade and is 40-fold more potent than glucose in mediating insulin resistance [Marshall, S., et al (1991), J. Biol Chem 266:4706-4712; reviewed in Marshall S. et al (1991), FASEB J. 5: 3031-3036; McClain D. A., Crook E. D. (1996), Diabetes 45: 1003-1009].
  • Preexposure to glucosamine induces insulin resistance in skeletal muscle; the tissue responsible for the majority of insulin-dependent glucose utilization.
  • TNF- ⁇ tumor necrosis factor- ⁇
  • a cytokine produced primarily by activated macrophages
  • adipocytes by adipocytes.
  • TNF- ⁇ is overexpressed in adipose tissues in many animal models of obesity-Type II diabetes [Hotamisligil G. S., Spiegelman B. M. (1994), Diabetes 43: 1271-1278; Hotamisligil G. S., et al (1993), Science 259: 87-91; Skolnik E. Y., Marcusohn J.
  • TNF- ⁇ treatment of cultured 3T3-L1 adipocytes provides a moderate reduction (20-50%) of insulin-stimulated insulin receptor autophosphorylation and a more pronounced effect on IRS-1 phosphorylation [Hotamisligil G. S. et al (1994), Proc. Natl. Acad. Sci. USA 91: 4854-4858; Feinstein R. et al (1993), J. Biol. Chem. 268: 26055-26058]. It has also been suggested that TNF- ⁇ induces insulin resistance via increased serine and threonine phosphorylation of IRS-1 [Hotarnisligil G. S. et al (1996), Science 271: 665-668; Kanety H. et al (1995), J. Biol. Chem. 270: 23780-23784].
  • Hyperglycemia and hyperinsulinemia may induce oxidative stress by increased generation of free radicals and reactive oxygen species (ROS) and/or impaired antioxidant defense systems [Wolff S. P., Dean R. T. (1987), Biochem J. 245: 243-250; Kashiwagi A. et al (1994), Diabetologia 37: 264-269; Wohaieb S. A., Godin D. V. (1987), Diabetes 36: 1014-1018].
  • ROS reactive oxygen species
  • Hyperglycemia-induced insulin resistance has also been reported to involve at least in part activation of protein kinase C (PKC) [Muller H. K.
  • Type II diabetes includes dietary control, exercise, and stimulation of insulin secretion by oral sulphonylureas.
  • oral drug therapy aimed at controlling hyperglycemia in NIDDM often fails, insulin therapy is necessary in the late phase of type II diabetes.
  • insulin resistance does not completely overcome the major defect in type II diabetes: insulin resistance. Therefore, compounds that can correct insulin resistance may be useful in the treatment of NIDDM.
  • N-acetyl cysteine N-acetyl cysteine
  • the present invention relates to a method of increasing insulin sensitivity or reducing insulin resistance in a subject comprising administering an effective amount of N-acetyl cysteine.
  • N-acetyl cysteine provides an increase in insulin sensitivity or reduced insulin resistance i.e. an increase in response to a given concentration of insulin.
  • the increase in insulin sensitivity/reduction in insulin resistance may be manifested as an increased ability of insulin to stimulate glucose uptake into muscle and fat, an inhibition of glucose production by the liver, an increase in insulin receptor and IRS-1 phosphorylation, increased PI 3-kinase activity, improved glucose transporter translocation, and/or stimulation of glycogen synthesis.
  • a method for preventing or treating a condition requiring increasing insulin sensitivity or reducing insulin resistance in a subject comprising administering to the subject an effective amount of N-acetyl cysteine.
  • the invention further provides a pharmaceutical composition for use in preventing or treating a condition requiring increasing insulin sensitivity comprising an effective amount of N-acetyl cysteine, and a pharmaceutically acceptable carrier, diluent, or excipient.
  • the pharmaceutical compositions of the invention contain one or more active ingredient, as described herein, either alone or together with other active substances.
  • Such pharmaceutical compositions can be for oral, topical, rectal, parenteral, local, inhalant or intracerebral use. They are therefore in solid or semisolid form, for example pills, tablets, creams, gelatin capsules, capsules, suppositories, soft gelatin capsules, gels, membranes, tubelets.
  • those forms for intramuscular or subcutaneous administration can be used, or forms for infusion or intravenous or intracerebral injection can be used, and can therefore be prepared as solutions of the active substances or as powders of the active substances to be mixed with one or more pharmaceutically acceptable excipients or diluents, suitable for the aforesaid uses and with an osmolarity which is compatible with the physiological fluids.
  • those preparations in the form of creams or ointments for topical use or in the form of sprays should be considered; for inhalant uses, preparations in the form of sprays, for example nose sprays, should be considered.
  • the preparations of the invention can be intended for administration to humans or animals.
  • the dosage administered will vary depending on the use and known factors such as the pharmacodynamic characteristics of the particular substance, and its mode and route of administration; age, health, and weight of the individual recipient; nature and extent of symptoms, kind of concurrent treatment, frequency of treatment, and the effect desired.
  • an oral dose of between 100 mg-10 g, preferably 400 mg to 4 g, most preferably, 400 to 1600 mg of NAC daily (oral) is administered to a subject to prevent or treat conditions requiring increased insulin sensitivity or reduced insulin resistance in the subject.
  • compositions can be prepared by per se known methods for the preparation of pharmaceutically acceptable compositions which can be administered to patients, and such that an effective quantity of the active substance is combined in a mixture with a pharmaceutically acceptable vehicle.
  • Suitable vehicles are described, for example, in Remington's Pharmaceutical Sciences (Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., USA 1985).
  • the pharmaceutical compositions include, albeit not exclusively, solutions of NAC in association with one or more pharmaceutically acceptable vehicles or diluents, and contained in buffered solutions with a suitable pH and iso-osmotic with the physiological fluids.
  • the active substance (i.e. NAC) or pharmaceutical compositions of the invention can be administered either alone or in conjunction with other therapeutic agents or other forms of therapy.
  • the active substance or pharmaceutical composition can be used in combination with, for example, a suitable, biologically active form of chromium, vanadium, magnesium, manganese, lithium, zinc, potassium, or other minerals capable of exerting an influence upon carbohydrate metabolism; with vitamins C, E, or lipoic acid, carotenoids, CoEnzyme Q10, glutathione and its esters, other forms of cysteine or other biological antioxidants; with concentrates, extracts, or phytochemicals derived from plants e.g.
  • the active substance of the invention may be administered concurrently, separately, or sequentially with other therapeutic agents or therapies.
  • compositions and methods of the invention may be used to treat conditions requiring increasing insulin sensitivity or which are associated with insulin resistance however caused (including by free fatty acids and tumor necrosis factor- ⁇ ), and/or to prevent such conditions.
  • Examples of such conditions include Type II diabetes, glucocorticoid induced insulin resistance, and obesity.
  • FIG. 1 is a graph showing the effect of NAC to reverse/prevent the high insulin and high glucose induced insulin resistance
  • FIG. 2 is a graph showing the lack of effect of NAC on control cells
  • FIG. 3 is a graph showing that glucosamine also causes insulin resistance (%Basal);
  • FIG. 4 is a graph of the data in FIG. 3 expressed as % maximum
  • FIG. 5 is a graph showing the effect of NAC to prevent/reverse the glucosamine induced insulin resistance
  • FIG. 6 is a graph showing that NAC was able to prevent insulin resistance induced by glucosamine in the intact rat.
  • Freshly isolated adipocytes were incubated in 1% BSA-DMEM (pH 7.4) in 250 ml conical culture flasks at 37° C. with cells floating on top of the medium in a thin layer. Cells were incubated for 18 hours in a humidified atmosphere of 5% CO 2 and air. For control cells, the medium contained no insulin and 5.6 mM D-glucose. To induce insulin resistance, 600 ng/ml (10 ⁇ 7 M) insulin and 20 mM D-glucose, or in the case of glucosamine 2.5 mM, were present in the medium.
  • Sprague-Dawley rats weighing 350-400 g were anesthetized and catheters were placed into the right internal jugular and left carotid arteries. The rats were allowed to recover for 5-7 days. Infusions of saline (control), or glucosamine (30 mmol/kg/min), with and without NAC (150 mg/kg over 1 hour, followed by 20 mg/kg/h) were carried out in awake, nonstressed rats for 7 hours. Two euglycemic clamps were performed consisting of an insulin infusion of 108 pmol/kg/min and adjusting the infusion rate of a 25% glucose solution to maintain normal glucose concentrations.
  • the first clamp was carried out between 0-2 hours and the second between 5-7 hours, i.e. at the beginning and the end of the 7h infusion period. These procedures have been previously described [Miles, PDG, et al, (1988), Diabetes 47:395-400; and Rossetti, C. et al (1995), J. Clin. Invest. 96:132-140].
  • the infusion rate of glucose at steady state that is, the final 30 min of the 2 hour clamp period, represents the glucose disposal rate and insulin sensitivity of peripheral tissues (mainly skeletal muscle) since at these insulin infusion rates hepatic glucose production is completely suppressed.
  • Euglycemic hyperinsulinemic clamps at 6-8 h revealed that hyperglycemia caused IR which was prevented by coinfusion of NAC (glucose uptake, mg/kg/min: control 43.8′′ 1.1; Resist 30.5′′ 1.5; Rest+NAC 45.6′′ 0.3; p ⁇ 0.01, Resist vs others). NAC alone had no effect. High G/I—mediated IR is prevented by NAC and GSH ester, but not by Vit E or Vit C. The data indicate a specific role for GSH in the pathogenesis of IR and NAC as a novel therapeutic agent.
  • NAC N-acetylcysteine
  • Insulin resistance is prevented by NAC in isolated rat adipocytes (adip) cultured in high glucose plus insulin (high G/I) and in rats infused with glucose.
  • the mechanism of high G/I mediated IR has been suggested to involve enhanced flux through the hexosamine biosynthesis pathway (HBP) via glutamine fructose amidotransferase and increased synthesis of UDP-N acetylhexosamines (UDP-HexNAc) as IR is induced by glucosamine.
  • HBP hexosamine biosynthesis pathway
  • UDP-HexNAc UDP-N acetylhexosamines
  • adip were rendered insulin resistant by exposure to 5.0 mM glucosamine and rats were infused with glucosamine for 7 h with a euglycernic hyperinsulinemic clamp performed during the first and final 2 h.
  • Coincubation of adip with NAC and coinffusion of NAC with glucosamine completely prevented IR in vitro and in vivo. NAC alone had no effect.
  • NAC prevents both high G/I and glucosamine-induced IR in vitro and in vivo 2) reversal of ATP depletion but not the elevated UDP-HexNAc associated with glucosamine prevents IR, while 3) NAC prevents IR and the associated increase in UDP-HexNAc induced by high G/I. NAC is indicated as a novel therapy for IR.

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US20040014692A1 (en) * 2001-12-20 2004-01-22 Debasis Bagchi Compositions incorporating(-)-hydroxycitric acid, chromium, and gymnemic acid, and related methods for promoting healthy body weight and improving related health factors
US20040137090A1 (en) * 2003-01-14 2004-07-15 Wright Jonathan V. Formulation for insulin and glucose control
US20040157929A1 (en) * 2002-04-01 2004-08-12 Ohia Sunny E. Method for increasing serotonin levels in a person by administration of a composition incorporating(-)hydroxycitric acid, and related compositions thereof
US20040186181A1 (en) * 2003-03-21 2004-09-23 Interhealth Nutraceuticals, Incorporated Method and composition for decreasing ghrelin levels
US20050215644A1 (en) * 2004-03-19 2005-09-29 Interhealth Nutraceuticals, Inc. Methods for increasing neurotransmitter levels using hydroxycitric acid
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US20060088592A1 (en) * 2004-04-28 2006-04-27 Seung-Ho Choi Oral formulation for delivery of poorly absorbed drugs
US20060105984A1 (en) * 2004-11-16 2006-05-18 Hwang David L Chromium complex with insulin-like activity
US20070015686A1 (en) * 2005-07-07 2007-01-18 Heuer Marvin A Dietary supplement for enhancing skeletal muscle mass, decreasing muscle protein degradation, downregulation of muscle catabolism pathways, and decreasing catabolism of muscle cells
US20070083369A1 (en) * 2005-10-06 2007-04-12 Mcculler Patrick Generating words and names using N-grams of phonemes
US20070118916A1 (en) * 2005-10-14 2007-05-24 Metanomics Gmbh Process for the production of fine chemicals
US20070270350A1 (en) * 2003-12-23 2007-11-22 Musc Foundation For Research Development Methods and Compositions for the Prevention and Treatment of Inflammatory Diseases or Conditions
US20080102137A1 (en) * 2006-10-31 2008-05-01 Guffey Manning V R Composition and method for etiological treatment and prevention of diseases and/or complications associated with chronic glucose metabolism destabilization
US20090253641A1 (en) * 2008-02-07 2009-10-08 Neufer P Darrell Methods for preventing or treating insulin resistance
US20090298923A1 (en) * 2008-05-13 2009-12-03 Genmedica Therapeutics Sl Salicylate Conjugates Useful for Treating Metabolic Disorders
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US9585898B2 (en) 2008-02-11 2017-03-07 Kenneth O. Russell Method for the reduction of dangerous blood sugar levels

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